Nanomedicine and Drug Delivery Strategies for Treatment of Genetic Diseases

Hsu, Janet; Muro, Silvia

doi:10.5772/24366

Cited by 4 publications

(6 citation statements)

References 115 publications

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“…77–80 Even so, the purported benefits of nonviral over viral gene delivery systems almost always include that nonviral systems are less immunogenic than viral systems, 81–87 with the chief drawback of nonviral systems being a lack of comparable transfection and expression efficiency. Indeed, nonviral carriers have been used to specifically deliver anti-inflammatory drugs.…”

Section: Discussionmentioning

confidence: 99%

“…It is well appreciated that the presence of free DNA in different cellular spaces, notably the cytosol that is normally void of DNA, has been shown to induce antiviral responses. − Even so, the purported benefits of nonviral over viral gene delivery systems almost always include that nonviral systems are less immunogenic than viral systems, − with the chief drawback of nonviral systems being a lack of comparable transfection and expression efficiency. Indeed, nonviral carriers have been used to specifically deliver anti-inflammatory drugs .…”

Section: Discussionmentioning

confidence: 99%

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Polyplex Exposure Inhibits Cell Cycle, Increases Inflammatory Response, and Can Cause Protein Expression without Cell Division

et al. 2013

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We sought to evaluate the relationship between cell division and protein expression when using commercial poly(ethylenimine) (PEI)-based polyplexes. The membrane dye PKH26 was used to assess cell division, and cyan fluorescent protein (CFP) was used to monitor protein expression. When analyzed at the whole population level, a greater number of cells divided than expressed protein, regardless of the level of protein expression observed, giving apparent consistency with the hypothesis that protein expression requires cells to pass through mitosis in order for the transgene to overcome the nuclear membrane. However, when the polyplex-exposed population was evaluated for the amount of division in the protein-expressing subpopulation, it was observed that substantial amounts of expression had occurred in the absence of division. Indeed, in HeLa S3 cells, this represented the majority of expressing cells. Of interest, the doubling time for both cell lines was slowed by ~2-fold upon exposure to polyplexes. This change was not altered by the origin of the plasmid DNA (pDNA) transgene promoter (cytomegalovirus (CMV) or elongation factor-1 alpha (EF1α)). Gene expression arrays in polyplex-exposed HeLa S3 cells showed upregulation of cell cycle arrest genes and downregulation of genes related to mitosis. Chemokine, interleukin, and toll-like receptor genes were also upregulated, suggesting activation of proinflammatory pathways. In summary, we find evidence that a cell division-independent expression pathway exists, and that polyplex exposure slows cell division and increases inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Polyplex Exposure Inhibits Cell Cycle, Increases Inflammatory Response, and Can Cause Protein Expression without Cell Division

et al. 2013

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“…3 In some disorders where multiple organ systems are affected, non-specific active targeting can enhance ubiquitous delivery of nanocarriers throughout the body. 33,34 This can be achieved by relying on non-specific interactions of nanocarriers toward general biological features, such as in the case of positively-charged moieties in HIV Tat peptide, RGD counterparts, antennapedia, and other sequences that can provide affinity to the negatively-charged plasmalemma of cells. 3,35 Coating nanocarriers with cationic polymers, such as chitosan, serves a similar purpose.…”

Section: Targeting Strategiesmentioning

confidence: 99%

“…the blood-brain barrier (BBB), and immunogenicity with production of antibodies against recombinant enzymes. 33,87 Several approaches have focused on overcoming these caveats, including optimization of enzyme glycosylation, modification of said residues, or enhancement of mannose or M6P receptor expression to improve enzyme targeting. 67,[88][89][90] Enzyme targeting via glycosylation-independent mechanisms is another option.…”

Section: Clinical and Experimental Treatmentsmentioning

confidence: 99%

Lysosomes and Nanotherapeutics: Diseases, Treatments, and Side Effects

Manthe

Muro

2014

Frontiers in Nanobiomedical Research

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Endolysosomal-related organelles, such as lysosomes, phagosomes, autophagosomes, and others, are essential to numerous cell processes; hence, their defective function associates with a number of diseases. For instance, lysosomal storage disorders are a group of about 50 genetic diseases characterized by lysosomal accumulation of undigested substrates, resulting in damage to peripheral organs and the central nervous system. Lysosomal aberrations are also implicated in autophagy-mediated disease progression, such as in cancer, neurodegenerative conditions (Alzheimer's, Parkinson's, and Huntington's diseases), auto-immune defects, and infl ammatory diseases. Although several treatment modalities help alleviate symptoms and improve quality of life for patients affected by these conditions, these therapies are still suboptimal in normalizing lysosomal-related functions. In order to overcome this caveat, strategies employing nanoscale drug delivery systems are being investigated. This chapter aims to review the features of lysosome-related diseases, the limitations of current treatments, and the potential utility of drug carriers to improve these strategies. A basic review of drug delivery vehicles is provided, along with considerations on the importance of proper carrier design and evaluation of the potential lysosomal toxicity associated with drug delivery systems. Handbook of Nanobiomedical Research Downloaded from www.worldscientific.com by KAINAN UNIVERSITY on 02/02/15. For personal use only.

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“…7, 10, 11 An example of such an approach is that of targeting intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein which is expressed on the vascular endothelium and most other cell types 12, 13 and over-expressed in most pathological states. ICAM-1 targeting provides transport of drug nanocarriers across cellular barriers and into lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Enhancing Biodistribution of Therapeutic Enzymes In Vivo by Modulating Surface Coating and Concentration of ICAM-1-Targeted Nanocarriers

Hsu¹,

Bhowmick²,

Burks³

et al. 2014

j biomed nanotechnol

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Coupling therapeutic proteins to targeted nanocarriers can enhance their biodistribution. This is the case for enzyme replacement therapies where intravenously injected enzymes must avoid prolonged blood exposure while reaching body organs. We have shown enhanced tissue targeting of various lysosomal enzymes by coupling to nanocarriers targeted to intercellular adhesion molecule-1 (ICAM-1). Here, we varied design parameters to modify tissue enzyme levels without affecting specific targeting and relative biodistribution. We coupled α-galactosidase (αGal; affected in Fabry disease) to model polymer nanocarriers and varied enzyme load (50 vs. 500 molecules/particle), anti-ICAM surface density (80 vs. 180 molecules/particle), and nanocarrier concentration (1.6×1013 vs. 2.4×1013 carriers/kg) to render three formulations (45, 449, 555 μg αGal/kg). Naked αGal preferentially distributed in blood vs. organs, while nanocarriers shifted biodistribution from blood to tissues. Accumulation in brain, kidneys, heart, liver, lungs, and spleen did not vary among nanocarrier formulations, with enhanced specific tissue accumulation compared to naked αGal. The highest specificity was associated with lowest antibody density and nanocarrier concentration, but highest enzyme load; possibly because of synergistic enzyme affinity toward cell-surface markers. Variation of these parameters significantly increased absolute enzyme accumulation. This strategy may help optimize delivery of lysosomal enzyme replacement and, likely, other protein delivery approaches.

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Nanomedicine and Drug Delivery Strategies for Treatment of Genetic Diseases

Cited by 4 publications

References 115 publications

Polyplex Exposure Inhibits Cell Cycle, Increases Inflammatory Response, and Can Cause Protein Expression without Cell Division

Polyplex Exposure Inhibits Cell Cycle, Increases Inflammatory Response, and Can Cause Protein Expression without Cell Division

Lysosomes and Nanotherapeutics: Diseases, Treatments, and Side Effects

Enhancing Biodistribution of Therapeutic Enzymes In Vivo by Modulating Surface Coating and Concentration of ICAM-1-Targeted Nanocarriers

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